Comparative Effects of Vaporized Perfluorohexane and Partial Liquid Ventilation in Oleic Acid- induced Lung Injury

Background: It is currently not known whether vaporized perfluorohexane is superior to partial liquid ventilation (PLV) for therapy of acute lung injury. In this study, the authors compared the effects of both therapies in oleic acid-induced lung injury.

Methods: Lung injury was induced in 30 anesthetized and mechanically ventilated pigs by means of central venous infusion of oleic acid. Animals were assigned to one of the following groups: (1) control or gas ventilation (GV), (2) 2.5% perfluorohexane vapor, (3) 5% perfluorohexane vapor, (4) 10% perfluorohexane vapor, or (5) PLV with perfluorooctane (30 ml/kg). Two hours after randomization, lungs were recruited and positive end-expiratory pressure was adjusted to obtain minimal elastance. Ventilation was continued during 4 additional hours, when animals were killed for lung histologic examination.

Results: Gas exchange and elastance were comparable among vaporized perfluorohexane, PLV, and GV before the open lung approach was used and improved in a similar fashion in all groups after positive end-expiratory pressure was adjusted to optimal elastance (P < 0.05). A similar behavior was observed in functional residual capacity (FRC) in animals treated with vaporized perfluorohexane and GV. Lung resistance improved after recruitment (P < 0.05), but values were higher in the 10% perfluorohexane and PLV groups as compared with GV (P < 0.05). Interestingly, positive end-expiratory pressure values required to obtain minimal elastance were lower with 5% perfluorohexane than with PLV and GV (P < 0.05). In addition, diffuse alveolar damage was significantly lower in the 5% and 10% perfluorohexane vapor groups as compared with PLV and GV (P < 0.05).     

Inhibition of Poly(Adenosine Diphosphate-Ribose) Polymerase Attenuates Ventilator-induced Lung Injury

Background: Mechanical ventilation can induce organ injury associated with overwhelming inflammatory responses. Excessive activation of poly(adenosine diphosphate-ribose) polymerase enzyme after massive DNA damage may aggravate inflammatory responses. Therefore, the authors hypothesized that the pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase by PJ-34 would attenuate ventilator-induced lung injury.

Methods: Anesthetized rats were subjected to intratracheal instillation of lipopolysaccharide at a dose of 6 mg/kg. The animals were then randomly assigned to receive mechanical ventilation at either low tidal volume (6 ml/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (15 ml/kg) with zero positive end-expiratory pressure, in the presence and absence of intravenous administration of PJ-34.

Results: The high-tidal-volume ventilation resulted in an increase in poly(adenosine diphosphate-ribose) polymerase activity in the lung. The treatment with PJ-34 maintained a greater oxygenation and a lower airway plateau pressure than the vehicle control group. This was associated with a decreased level of interleukin 6, active plasminogen activator inhibitor 1 in the lung, attenuated leukocyte lung transmigration, and reduced pulmonary edema and apoptosis. The administration of PJ-34 also decreased the systemic levels of tumor necrosis factor [alpha] and interleukin 6, and attenuated the degree of apoptosis in the kidney.     

Isoflurane-Sevoflurane Administration before Ischemia Attenuates Ischemia-Reperfusion-induced Injury in Isolated Rat Lungs

Background: The effects of volatile anesthetics on ischemia-reperfusion (IR)-induced lung injury are not clear. The authors investigated the effects of preadministration of isoflurane and sevoflurane on IR-induced lung injury in an isolated buffer-perfused rat lung model.

Methods: Isolated rat lungs were designated into four groups: control group (n = 6): perfusion for 120 min without ischemia; IR group (n = 6): interruption of perfusion and ventilation for 60 min followed by reperfusion for 60 min; sevoflurane (SEVO)-IR (n = 6) and isoflurane (ISO)-IR (n = 6) groups: 1 minimum alveolar concentration (MAC) isoflurane or sevoflurane was administered for 30 min, followed by 60 min ischemia, then 60 min reperfusion. The authors measured the coefficient of filtration (Kfc) of the lung, lactate dehydrogenase (LDH) activity, tumor necrosis factor [alpha], and nitric oxide metabolites (nitrite + nitrate) in the perfusate and the wet-to-dry lung weight ratio.

Results: IR caused significant increases in the coefficient of filtration (approximately sevenfold at 60 min of reperfusion compared with baseline;P < 0.01), the wet-to-dry lung weight ratio, the rate of increase of lactate dehydrogenase activity, and tumor necrosis factor [alpha] in the perfusate, and caused a significant decrease in nitric oxide metabolites in the perfusate. Administration of 1 MAC isoflurane or sevoflurane before ischemia significantly attenuated IR-induced increases in the coefficient of filtration and the wet-to-dry lung weight ratio, inhibited increases in the rate of increase of lactate dehydrogenase activity and tumor necrosis factor [alpha] in the perfusate, and abrogated the decrease in nitric oxide metabolites in the perfusate. No difference was found between the SEVO-IR and ISO-IR groups.     

Role of Potassium Channels in Isoflurane- and Sevoflurane-induced Attenuation of Hypoxic Pulmonary Vasoconstriction in Isolated Perfused Rabbit Lungs

Background: Although potassium channels are thought to be responsible for the initiation of hypoxic pulmonary vasoconstriction (HPV), their role in the HPV-inhibitory effect of volatile anesthetics is unclear. The current study tested if the HPV-inhibitory effect of isoflurane and sevoflurane can be affected by changing the potassium-channel opening status with specific potassium-channel inhibitors in isolated rabbit lungs.

Methods: Isolated rabbit lungs were divided into eight groups (n = 6 each in isoflurane groups and n = 8 in sevoflurane groups): those receiving no inhibitor treatment = control-isoflurane and control-sevoflurane groups; those treated with an adenosine triphosphate-sensitive potassium (KATP)-channel inhibitor, glibenclamide = glibenclamide-isoflurane and glibenclamide-sevoflurane groups; those treated with a high-conductance calcium-activated potassium (KCa)-channel inhibitor, iberiotoxin = iberiotoxin-isoflurane and iberiotoxin-sevoflurane groups; and those treated with a voltage-sensitive potassium (KV)-channel inhibitor, 4-aminopyridine = 4-aminopyridine-isoflurane and 4-aminopyridine-sevoflurane groups. The effect of anesthetic on HPV was tested by exposure of the lungs to isoflurane at a concentration of 0, 0.5, 1, or 2 minimum alveolar concentration, or to sevoflurane at a concentration of 0, 0.5, 1, or 1.62 minimum alveolar concentration. The relation between anesthetic concentrations and the HPV response was analyzed by the Wagner equation.

Results: The inhibition of KV channels by 4-aminopyridine and KCa channels by iberiotoxin augmented the HPV response. The isoflurane-induced attenuation of HPV was attenuated by voltage-sensitive potassium-channel inhibition with 4-aminopyridine, potentiated by KCa-channel inhibition with iberiotoxin, but not affected by KATP-channel inhibition with glibenclamide. The sevoflurane-induced attenuation of HPV was not affected by any of the potassium-channel inhibitors.     

Sodium Nitrite Mitigates Ventilator-induced Lung Injury in Rats

BACKGROUND:: Nitrite (NO2) is a physiologic source of nitric oxide and protects against ischemia-reperfusion injuries. We hypothesized that nitrite would be protective in a rat model of ventilator-induced lung injury and sought to determine if nitrite protection is mediated by enzymic catalytic reduction to nitric oxide. METHODS:: Rats were anesthetized and mechanically ventilated. Group 1 had low tidal volume ventilation (LVT) (6 ml/kg and 2 cm H2O positive end-expiratory pressure; n = 10); group 2 had high tidal volume ventilation (HVT) (2 h of 35 cm H2O inspiratory peak pressure and 0 cm H2O positive end-expiratory pressure; n = 14); groups 3-5: HVT with sodium nitrite (NaNO2) pretreatment (0.25, 2.5, 25 μmol/kg IV; n = 6-8); group 6: HVT + NaNO2 + nitric oxide scavenger 2-(4-carboxyphenyl)-4,5dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3oxide(n = 6); group 7: HVT + NaNO2 + nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (n = 7); and group 8: HVT + NaNO2 + xanthine oxidoreductase inhibitor allopurinol (n = 6). Injury assessment included physiologic measurements (gas exchange, lung compliance, lung edema formation, vascular perfusion pressures) with histologic and biochemical correlates of lung injury and protection. RESULTS:: Injurious ventilation caused statistically significant injury in untreated animals. NaNO2 pretreatment mitigated the gas exchange deterioration, lung edema formation, and histologic injury with maximal protection at 2.5 μmol/kg. Decreasing nitric oxide bioavailability by nitric oxide scavenging, nitric oxide synthase inhibition, or xanthine oxidoreductase inhibition abolished the protection by NaNO2. CONCLUSIONS:: Nitrite confers protection against ventilator-induced lung injury in rats. Catalytic reduction to nitric oxide and mitigation of ventilator-induced lung injury is dependent on both xanthine oxidoreductase and nitric oxide synthases.     

From Continuous Positive-pressure Breathing to Ventilator-induced Lung Injury

Continuous positive-pressure ventilation in acute respiratory failure. By Kumar A, Falke KJ, Geffin B, Aldredge CF, Laver MB, Lowentein E, Pontoppidan H. N Engl J Med 1970; 283:1430-6. Reprinted with permission.     

Hypoxia-induced Vasoconstriction in Isolated Perfused Lungs exposed to Injectable or Inhalation Anesthetics

Investigations during the last two decades have revealed a tendency to impaired pulmonary gas exchange in patients during general anesthesia. In the awake state, arterial hypoxemia is counteracted by a mechanism which tends to normalize the ventilation perfusion ratio of the lungs by way of a hypoxia-induced vasoconstriction in poorly ventilated areas. This results in a redistribution of perfusion to more adequately ventilated lung regions. Recent observations suggest, however, that this beneficial mechanism is blunted by some commonly used inhalation anesthetics.
In the present study the effects of inhalation anesthetics and injectable anesthetics on the vasoconstrictor response to acute alveolar hypoxia have been compared in isolated blood-perfused rat lungs. The experiments showed that the response was unaffected by N₂O and injectable anesthetics, while a reversible, dose-dependent damping effect was demonstrated for the volatile inhalation anesthetics, ether, halothane and methoxyflurane. The effect could be demonstrated at blood concentrations comparable to those used in clinical anesthesia, and it was not due to a general paralysis of the vascular smooth muscle. The findings might, at least in part, explain the occurrence of arterial hypoxemia during general inhalation anesthesia.     

Regional Gas Exchange and Cellular Metabolic Activity in Ventilator-induced Lung Injury

Background: Alveolar overdistension and repetitive derecruitment-recruitment contribute to ventilator-induced lung injury (VILI). The authors investigated (1) whether inflammatory cell activation due to VILI was assessable by positron emission tomography and (2) whether cell activation due to dynamic overdistension alone was detectable when other manifestations of VILI were not yet evident.

Methods: The authors assessed cellular metabolic activity with [18F]fluorodeoxyglucose and regional gas exchange with [13N]nitrogen. In 12 sheep, the left ("test") lung was overdistended with end-inspiratory pressure of 50 cm H2O for 90 min, while end-expiratory derecruitment of this lung was either promoted with end-expiratory pressure of -10 cm H2O in 6 of these sheep (negative end-expiratory pressure [NEEP] group) or prevented with +10 cm H2O in the other 6 (positive end-expiratory pressure [PEEP] group) to isolate the effect of overdistension. The right ("control") lung was protected from VILI.

Results: Aeration decreased and shunt fraction increased in the test lung of the NEEP group. [18F]fluorodeoxyglucose uptake of this lung was higher than that of the control lung and of the test lung of the PEEP group, and correlated with neutrophil count. When normalized by tissue fraction to account for increased aeration of the test lung in the PEEP group, [18F]fluorodeoxyglucose uptake was elevated also in this group, despite the fact that gas exchange had not yet deteriorated after 90 min of overdistension alone.     

中度低温减轻内毒素性急性肺损伤大鼠肺炎症反应

Thesyndromeofacutelunginjury (ALI)isinitiatedbyavarietyoflocalorsystemicinsultsleadingtodiffusedamagetothepulmonaryparenchyma .Ithasbeenprop osedthatALIistheoutcomeofanuncontrolledinflamma toryresponseinwhichinflammatorycytokinesplayaveryimportantrole .ModulatingtheinflammatoryresponseofALImaybeoftherapeuticbenefit.Arecentstudyshowsthatmoderatehypothermiareducestheproductionofcyto kinesandinhibitstheinflammatoryresponseafteracutehemorrhageinrats .1Therefore ,wetestedthehypothesisthathypoth…     

Comparative Cardiac Effects of Terlipressin, Vasopressin, and Norepinephrine on an Isolated Perfused Rabbit Heart

Background: Terlipressin, a synthetic analog of arginine-vasopressin (AVP), has been proposed as an effective vasopressive therapy in catecholamine-resistant vasodilatory shock. Although beneficial effects of terlipressin on systemic arterial pressure have been clearly demonstrated, its intrinsic effects on coronary circulation and myocardial performances remain unknown.

Methods: The authors compared the coronary and myocardial effects of terlipressin (1-100 nm, n = 10), AVP (10-1000 pm, n = 10), and norepinephrine (1-100 nm, n = 10) on an erythrocyte-perfused isolated rabbit heart. The cardiac effects of terlipressin were also assessed in erythrocyte-perfused hearts in which the myocardial oxygen delivery was maintained constant and buffer-perfused hearts. Finally, the cardiac effects of terlipressin and AVP were studied in hearts pretreated by [d(CH2)5Tyr(Me)]AVP (0.1 [mu]m), a selective V1a receptor antagonist.

Results: Norepinephrine induced a biphasic coronary effect associated with a concentration-dependent increase in myocardial performances. AVP and terlipressin significantly decreased coronary blood flow and impaired myocardial performances from 30 pm and 30 nm, respectively (P < 0.05). The cardiac side-effects of terlipressin were confirmed in buffer-perfused hearts but the maintenance of a constant myocardial oxygen delivery constant abolished its effects on myocardial performances. The cardiac effects induced by terlipressin and AVP were nearly completely abolished on hearts pretreated by [d(CH2)5Tyr(Me)]AVP.     

Effects of Peak Inspiratory Flow on Development of Ventilator-induced Lung Injury in Rabbits

Background: A lung-protecting strategy is essential when ventilating acute lung injury/acute respiratory distress syndrome patients. Current emphasis is on limiting inspiratory pressure and volume. This study was designed to investigate the effect of peak inspiratory flow on lung injury.

Methods: Twenty-four rabbits were anesthetized, tracheostomized, ventilated with a Siemens Servo 300, and randomly assigned to three groups as follows: 1) the pressure regulated volume control group received pressure-regulated volume control mode with inspiratory time set at 20% of total cycle time, 2) the volume control with 20% inspiratory time group received volume-control mode with inspiratory time of 20% of total cycle time, and 3) the volume control with 50% inspiratory time group received volume-control mode with inspiratory time of 50% of total cycle time. Tidal volume was 30 ml/kg, respiratory rate was 20 breaths/min, and positive end-expiratory pressure was 0 cm H2O. After 6 h mechanical ventilation, the lungs were removed for histologic examination.

Results: When mechanical ventilation started, peak inspiratory flow was 28.8 +/- 1.4 l/min in the pressure regulated volume control group, 7.5 +/- 0.5 l/min in the volume control with 20% inspiratory time group, and 2.6 +/- 0.3 l/min in the volume control with 50% inspiratory time group. Plateau pressure did not differ significantly among the groups. Gradually during 6 h, Pao2 in the pressure regulated volume control group decreased from 688 +/- 39 to a significantly lower 304 +/- 199 mm Hg (P < 0.05) (mean +/- SD). The static compliance of the respiratory system for the pressure regulated volume control group also ended significantly lower after 6 h (P < 0.05). Wet to dry ratio for the pressure regulated volume control group was larger than for other groups (P < 0.05). Macroscopically and histologically, the lungs of the pressure regulated volume control group showed more injury than the other groups.     

Apigenin Attenuates Inflammation in Experimentally Induced Acute Pancreatitis-Associated Lung Injury

Background: Acute pancreatitis is associated with acute lung injury. The aim of the present study is to evaluate alterations of lungs in an experimental model of acute pancreatitis (AP) following both bilio-pancreatic duct obstruction close to the duodenum. Acute pancreatitis is a common disease with significant mortality. This situation makes the need of finding protective factors for the lung parenchyma, imperative. In the present study there is an effort to clarify the role of apigenin, a substance which is well known for its antioxidant and anti-inflammatory effects, on lung injury, following acute pancreatitis in rats. Materials and methods: In the present study, 126 male Wistar-type rats 3–4 months old and 220–350 g weight were used. At time 0 we randomly assigned the following groups: Group Sham: Rats were subjected to virtual surgery. Group Control: Rats were subjected to surgery for induction of acute pancreatitis. Group Apigenin: Rats were subjected to surgery for induction of acute pancreatitis and enteral feeding with apigenin. Immunochemistry for TNF-α and IL-6 as well as MPO activity were measured at predetermined time intervals 6, 12, 24, 48, and 72 h, in order to evaluate architectural disturbances of the lung tissue. Results: From the pathological reports we realized that comparing the control group with the apigenin group, there is an improvement of lung tissue damage following apigenin administration, with statistical significance. Apigenin reduces most histopathological alterations of the pulmonary tissue, reduces MPO and TNF-α activity at 48 hours and, furthermore, reduces IL-6 activity at 72 hours post-administration. Conclusions: Oral Apigenin administration in rats, following experimental induced acute pancreatitis, seems to be protective on the lung tissue. Apigenin administration to humans could potentially ameliorate acute lung injuries. However, special caution is required for humans' use, as more detailed studies are needed.     

Neutrophil Stimulation with Granulocyte Colony-stimulating Factor Worsens Ventilator-induced Lung Injury and Mortality in Rats

Background: Based on the association between the neutrophil and ventilator-induced lung injury, the authors hypothesized that neutrophil inhibition with fucoidin would be beneficial and stimulation with granulocyte colony-stimulating factor (G-CSF) would be harmful in a rat model of lethal ventilator-induced lung injury.

Methods: Animals (n = 111) were randomly assigned to be pretreated with fucoidin, G-CSF, or placebo (control) before 4 h of low-tidal-volume (10 ml/kg) or high-tidal-volume (40 ml/kg) mechanical ventilation.

Results: All low-volume animals survived. With high volumes, compared with controls, fucoidin did not improve survival (3 of 20 control animals and 5 of 20 fucoidin animals died; P = 0.51) but G-CSF significantly worsened it (18 of 22 animals died; P < 0.001). Circulating neutrophils were increased early with G-CSF and late with fucoidin with low and high tidal volumes (P < 0.05 for each treatment and tidal volume). Fucoidin decreased lung neutrophils, but these were only significant with high tidal volumes, whereas G-CSF increased lung neutrophils but only significantly with low tidal volumes (P <= 0.01 for each). Fucoidin did not alter any cardiopulmonary measure significantly. Compared with control, G-CSF increased airway pressures with high tidal volumes and worsened lung edema and arterial oxygen with both tidal volumes (P < 0.05 for each).     

Autologous Transplantation of Endothelial Progenitor Cells Attenuates Acute Lung Injury in Rabbits

Background: Acute lung injury (ALI) and end-stage acute respiratory distress syndrome (ARDS) are among the most common causes of death in intensive care units. Activation and damage of pulmonary endothelium is the hallmark of ALI/ARDS. Recent studies have demonstrated the importance of circulating endothelial progenitor cells (EPCs) in maintaining normal endothelial function as well as endothelial repairing after vascular injury. Here, the authors present the first study demonstrating the therapeutic potential of EPCs in a rabbit model of ALI/ARDS.

Methods: Circulating EPCs were obtained from rabbits using Ficoll centrifugation. One week after culturing, ALI was induced in rabbits by oleic acid (75 mg/kg, intravenous), and autologous EPCs were transplanted intravenously. Vasomotor function of isolated pulmonary artery and degrees of lung injury were assessed 2 days later.

Results: Endothelial dysfunction in the pulmonary artery was significantly attenuated in rabbits treated with EPCs, whereas the endothelium-independent relaxation responses were not different. Expression of inducible nitric oxide synthase was suppressed in the pulmonary artery of EPC-treated animals. Infiltration of leukocytes in the lung parenchyma was significantly reduced after EPC transplantation. EPCs also decreased water content, hyaline membrane formation, and hemorrhage in lungs.